Platelet production compensates for changing peripheral requirements by modulating levels of endogenous thrombopoietin (TPO), the physiologic Mpl ligand stimulating hematopoietic stem cells to undergo megakaryocyte development, endoproliferation, and cytoplasmic differentiation. TPO levels increase with thrombocytopenia and fall after replacing platelets by transfusion. Although TPO production by liver and kidneys is not physiologically regulated, as shown by TPO-and Mpl-gene deletion studies, the binding of plasma TPO with available Mpl receptors on circulating platelets, constitutes a negative feed-back mechanism. Exogenous Mpl ligands, including recombinant human thrombopoietin (rHu-TPO, 332 glycosylated AAs), megakaryocyte growth and development factor (163 nonglycosylated AAs), and rHu-PEGMGDF (polyethylene glycol coupled MGDF) produce log-linear increases in megakaryocyte formation and endoreduplication, and transiently enhance platelet aggregatory responses ex vivo, without increasing thrombus formation. Thus, administering Mpl ligands during thrombocytopenia provides platelet hemostatic protection during thrombocytopenia without increasing thrombo-occlusive risks. [unreadable] P51RR00165-36 1/1/96 - 12/31/96 Yerkes Regional Primate Research Center